Drug Content Analysis Research Articles

Can intracellular drug delivery using hyaluronic acid functionalised pH-sensitive liposomes overcome gemcitabine resistance in pancreatic cancer?

Chemoresistance poses a major challenge in cancer treatment. This study aims to investigate whether intracellular drug delivery using hyaluronic acid (HA) functionalised pH-sensitive liposomes (HA-pSL) can circumvent gemcitabine resistance in pancreatic cancer (PC). HA-pSL were obtained by covalently conjugating HA with preformed pSL. A resistant PC cell line Gr2000 was developed by exposing MIA PaCa-2 cells to gemcitabine, and characterised for their expression of CD44, a receptor for HA, and drug transporters. Cellular uptake and intracellular trafficking of liposomes were determined by confocal microscopy and HPLC analysis of intracellular drug content. Following a pharmacokinetic study in rats, anti-tumour efficacy was compared between MIA PaCa-2 and Gr2000 xenograft mouse models. HA-pSL with an HA density of 179 μg/μmol had a larger size (152.3 vs 136.3 nm), and higher zeta potential (−46.8 vs −10.5 mV) than pSL. The sensitivity of Gr2000 to gemcitabine reduced 444 times compared to its parental cell line, despite no change to the total drug influx, as drug influx- and efflux-transporters in Gr2000 cells were simultaneously up-regulated. Both cell lines had high expression of CD44. HA facilitated cell uptake without compromising the endosome-escape ability of pSL as evidenced by confocal images and co-localization analysis of the dual-fluorescence labelled liposomes and Lysotracker. HA-pSL significantly outperformed pSL, and increased cellular drug influx by 3.6 times in MIA PaCa-2 cells, and 4.6 times in Gr2000 cells. Both liposomes improved the pharmacokinetic profile of free drug. HA-pSL treatment was superior to pSL, and resulted in 6.4 times smaller tumours (weight) in the MIA PaCa-2 xenograft models, and 3.1 smaller in the Gr2000 models compared with the free drug. Taken together, this study highlighted the use of intracellular delivery strategies (HA-CD44 interaction and endosome escape) to overcome gemcitabine resistance, however, the overall improvement was marginal and tumours still existed. Further improvement in delivery efficiency of HA-pSL to target tumours and additional manipulation of the cellular metabolism of gemcitabine are needed to tackle chemoresistance.

Cytotoxic Effect of Paclitaxel and Lapatinib Co-Delivered in Polylactide-co-Poly(ethylene glycol) Micelles on HER-2-Negative Breast Cancer Cells.

To find better strategies to enhance the cytotoxic effect of paclitaxel (PTX) and lapatinib (LAP) against breast cancer cells, we analyzed the efficacy of a novel delivery system containing polylactide-co-poly(ethylene glycol) (PLA-PEG) filomicelles of over 100 nm in length and spherical micelles of approximately 20 nm in diameter. The 1H NMR measurements confirmed the incorporation of PTX and LAP into micelles. Analysis of the drug release mechanism revealed the diffusion-controlled release of LAP and anomalous transport of PTX. Drug content analysis in lyophilized micelles and micellar solution showed their good storage stability for at least 6 weeks. Blank micelles, LAP-loaded micelles and free LAP did not affect MCF-7 breast cancer cell proliferation, suggesting that the cytotoxicity of PTX-, PTX/LAP-loaded micelles, and the binary mixture of free PTX and LAP was solely caused by PTX. PTX/LAP-loaded micelles showed greater toxicity compared to the binary mixture of PTX and LAP after 48 h and 72 h. Only free PTX alone induced P-gp activity. This study showed the feasibility of using a LAP and PTX combination to overcome MDR in MCF-7 cells, particularly when co-loaded into micelles. We suggest that PTX/LAP micelles can be applicable not only for the therapy of HER-2-positive, but also HER-2-negative breast cancers.

Formulation and evaluation of almotriptan controlled release pellets

Abstract: The aim of the present study was to formulate and evaluate Almotriptan pellets. Almotriptan controlled release pellets were prepared by Solution layering technique by using croscarmellose and povidone in former case and three different polymers HPMC K 100, Ethyl cellulose and Eudragit RS 100 as rate controlling polymer in three different ratios like 1:1, 1:1.5 and 1:2 to achieve desired release in later case. Evaluation was performed according to the Pharmacopoeia standards including Drug excipients compatibility, Percentage yield, Particle size distribution, Drug content analysis and in-vitro release study. The best results were found to be using Almotriptan and Eudragit RS 100 in 1:2 ratios. A broad variety of drug release pattern could be achieved by variation of polymers ratios which was optimized to match the target release profile. In comparison of in-vitro release studies for different controlled release formulations, F9 releases 98.54% of drug at the end of 12th hour and was considered as best formulation. Stability study has shown no significant change in the drug content analysis and in-vitro dissolution study of best formulation even after 6 months.
 Keywords: Almotriptan, Controlled release, Dissolution profile, in-vitro drug release, Stability studies.

Improvement of bone microarchitecture in methylprednisolone induced rat model of osteoporosis by using thiolated chitosan-based risedronate mucoadhesive film

Objective: In this study, we investigated the potential of thiolated chitosan-based mucoadhesive film, loaded with risedronate sodium in the treatment of osteoporosis.Significance: Risedronate sodium is a bisphosphonate derivative having very low bioavailability when administered through the oral route. Moreover, the adverse effects associated with the drug when administered through GIT necessitate an alternative and feasible route which can improve its bioavailability and therapeutic efficacy.Methods: Thiolation of chitosan was interpreted by different analytical techniques. The mucoadhesive films were prepared by the solvent evaporation method and evaluated for drug content analysis, swelling degree, mucoadhesive parameters, and permeation characterization. For the screening of preclinical efficacy and pharmacodynamic parameters, a methylprednisolone induced osteoporotic rat model was used. The trabecular microarchitecture and biochemical markers were evaluated for determination of bone resorption.Results: The different analytical characterization of synthesized thiolated chitosan revealed that chitosan was successfully incorporated with thiol groups. The formulation containing 2:1 ratio of thiolated chitosan and HPMC-4KM was found to have the maximum swelling degree, mucoadhesive strength with a good force of adhesion and better in vitro permeability compared to the marketed formulation. With respect to trabecular microarchitecture, the drug-loaded film formulation showed superior and promising results. Furthermore, the film formulation also improved the serum level of biomarkers better than the marketed formulation.Conclusions: The results significantly suggest that risedronate loaded novel mucoadhesive film formulation could be a logical approach in the therapeutic intervention of osteoporosis.

Solid state 13C NMR spectroscopy provides direct evidence for reaction between ethinyl estradiol and a silicone elastomer vaginal ring drug delivery system

Steroid molecules have a long history of incorporation into silicone elastomer materials for controlled release drug delivery applications. Previously, based on in vitro release testing and drug content analysis, we demonstrated indirectly that the contraceptive progestin levonorgestrel (LNG) chemically and irreversibly binds to addition cure silicone elastomers, presumably via a hydrosilylation reaction between the levonorgestrel ethynyl group and the hydrosilane groups in the poly(dimethylsiloxane-co-methylhydrosiloxane) crosslinker of the silicone elastomer. Here, for the first time, we report that solid state 13C nuclear magnetic resonance (NMR) spectroscopy provides direct evidence for the irreversible binding of ethinyl estradiol (EE) – an estrogenic steroid molecule also containing an ethynyl functional group – to an addition cure silicone elastomer. By preparing silicone elastomer samples containing 13C-labelled EE, signals in the NMR spectra could readily be assigned to both the free and bound EE. Additional depolymerisation studies, performed on an addition cure silicone elastomer system from which the unbound EE fraction was completely extracted, further confirmed the presence of bound EE through the formation of coloured reaction mixtures resulting from the reaction of bound EE and trifluoroacetic acid (TFA). These methods will be particularly useful in the ongoing development of new steroid-releasing silicone drug delivery devices, including various vaginal ring devices for contraception, HIV prevention and multipurpose prevention technology applications.

Nanostructured gel for topical delivery of azelaic acid: Designing, characterization, and in-vitro evaluation

The study is designed to formulate, optimize and evaluate Azelaic acid loaded nano-structured lipid carrier (NLCs) with an aim to enhance its skin targeting, retention, and achieve sustained release with reduced drug related side effects. NLCs were formulated by melt emulsification and ultra-sonication technique and optimized employing 33 full factorial design taking lipid:drug ratio, surfactant concentration and sonication time as independent variables with particle size (PS) and entrapment efficiency (EE) as dependent variables. The optimized formulation (F23) exhibited spherical surfaced stable nano particles of 49.6 ± 1.24 nm size and 83.4 ± 2.14% EE. Formulation F23 was then incorporate to aloe-vera based carbopol gel and evaluated for its physiological properties, drug content, in-vitro release and skin distribution (fluorescent microscopy) analysis. The gel was found to be non-irritating, homogenous, with optimum moisture content, spreadability and occlusivity. In-vitro permeation studies showed NLC preparation to markedly enhance the dug's skin retention in comparison to drug suspended in gel and marketed preparation. The skin distribution studies employing rhodamine 6G further confirmed the permeation of NLCs to the deeper layers of skin. The experimental findings suggested that NLCs could serve as a promising carrier for site specific targeting with better skin retention abilities.

ULTRA PERFORMANCE LIQUID CHROMATOGRAPHY: A REVOLUTIONIZED LC TECHNIQUE

High Performance Liquid Chromatography (HPLC) is a major technique for qualitative and quantitative drug analysis. More than 90% of drugs prescribed in official pharmacopoeias are being analyzed HPLC. HPLC analyzes the drug content in a sample with high degree of accuracy and precision. Due to the stringent regulatory requirements the number of samples for drug content analysis has been increased significantly. Therefore, pharmaceutical industries need a fast, accurate and affordable method for drug content analysis. Here, Ultra Performance Liquid Chromatography (U-PLC) offers an advancement of HPLC which is based on the principal of use of stationary phase consisting of particles less than 2μm. By using smaller particles; speed and peak capacity can be extended to new limits and the sample can be analyzes in a shorter period of time. It provides good resolution even for congeneric compounds. The present review discusses the various aspects of UPLC in pharmaceutical analysis.

Preparation and evaluation of curcumin-loaded self-assembled micelles

Objective: Curcumin being used to treat various chronic diseases while its poor bioavailability issue limited its wide clinical application as a therapeutic agent. The aim of this work was to prepare curcumin-loaded self-assembled micelles using soluplus and solutol®HS15 (SSCMs) to enhance curcumin’s solubility and thus oral bioavailability.Methods: Optimum formulation was investigated and the optimized ratio of drugs and excipients was obtained and the SSCMs were prepared via ethanol solvent evaporation method. The optimal SSCMs were characterized by transmission electron microscopy, drug content analysis including loading efficiency (LE%) and entrapment efficiency (EE%), and the cumulative amount of curcumin released from the micelles were all calculated using HPLC method. The in vitro cytotoxicity and the permeability of SSCMs were measured by Caco-2 cell monolayers and the oral bioavailability was evaluated by SD rats.Key findings: The solubility of curcumin in self-assembled micelles was dramatically increased by 4200 times as compared to free curcumin. Caco-2 cells transport experiment exhibited that while soluplus and solutol®HS15 were self-assembled into micelles, it could not only promote the permeability of curcumin across membrane for better absorption, but also could restrain the curcumin pumped outside due to the role of P-gp efflux mechanism of soluplus and solutol®HS15. Furthermore, the prepared SSCMs formulation was almost nontoxic and had safety performance on Caco-2 cells model. Moreover, curcumin’s oral bioavailability of SSCMs formulation in SD rats had doubled than that of free curcumin.Conclusions: The prepared SSCMs were characterized by PS, PDI, LE%, EE% data analysis. After the soluplus and solutol®HS15 were self assembled into micelles, both the solubility and membrane permeability of curcumin were evaluated to have been enhanced, as well as the effect of efflux pump of curcumin was inhibited, hence to promote oral absorption and generate an increased bioavailability.

Design of Extended Release Matrix Tablet of Tramadol hydrochloride Using Combination of Hydrophobic and Hydrophilic Polymer

The aim of design of oral extended drug delivery system is to achieve a prolonged therapeutic effect by continuously releasing medicament over an extended period of time after administration of a single dose. An attempt was made to formulate Tramadol Extended Release (ER) matrix tablet using combination of hydrophobic and hydrophilic polymer consisting of ethyl cellulose, HPMC K15M, carbopol, and xanthan gum. The polymeric concentration of hydrophobic and hydrophilic polymer was optimized and was found that drug to polymeric ratio (hydrophobic and hydrophilic) of 1:0.75:0.75 was appropriate for the formulation of Tramadol ER tablet. The concentration of hydrophobic polymer was kept constant were as the combination of hydrophilic polymer was attempted and combined to hydrophobic polymer to retard the drug release for 24-hour from the matrix tablet. A total of nine formulations (F1-F9) of Tramadol matrix tablet, with different concentration of hydrophobic and hydrophilic polymer were used with other excipients. The tablets were compressed by direct compression method after subjecting the blend to blend physical parameters studies like studies like angle of repose, bulk density, tapped density, Carr’s index. The results obtained were satisfactory. Post compression parameters like hardness, weight variation, friability, drug content analysis and in-vitro release profiles of drug from all the formulations could be best expressed by Higuchi’s equation, as the plots showed high linearity (R2: 0.942-0.995). To confirm the diffusion mechanism, the data were fit into Korsmeyer equation. The formulations F-1 to F-6 showed good linearity (R2: 0.961 to 0.993), which indicate the mechanism is diffusion coupled with erosion.

Analysis of lomustine drug content in FDA-approved and compounded lomustine capsules.

OBJECTIVE To determine the lomustine content (potency) in compounded and FDA-approved lomustine capsules. DESIGN Evaluation study. SAMPLE 2 formulations of lomustine capsules (low dose [7 to 11 mg] and high dose [40 to 48 mg]; 5 capsules/dose/source) from 3 compounders and from 1 manufacturer of FDA-approved capsules. PROCEDURES Lomustine content was measured by use of a validated high-pressure liquid chromatography method. An a priori acceptable range of 90% to 110% of the stated lomustine content was selected on the basis of US Pharmacopeia guidelines. RESULTS The measured amount of lomustine in all compounded capsules was less than the stated content (range, 59% to 95%) and was frequently outside the acceptable range (failure rate, 2/5 to 5/5). Coefficients of variation for lomustine content ranged from 4.1% to 16.7% for compounded low-dose capsules and from 1.1% to 10.8% for compounded high-dose capsules. The measured amount of lomustine in all FDA-approved capsules was slightly above the stated content (range, 104% to 110%) and consistently within the acceptable range. Coefficients of variation for lomustine content were 0.5% for low-dose and 2.3% for high-dose FDA-approved capsules. CONCLUSIONS AND CLINICAL RELEVANCE Compounded lomustine frequently did not contain the stated content of active drug and had a wider range of lomustine content variability than did the FDA-approved product. The sample size was small, and larger studies are needed to confirm these findings; however, we recommend that compounded veterinary formulations of lomustine not be used when appropriate doses can be achieved with FDA-approved capsules or combinations of FDA-approved capsules.

Preparation and evaluation of enteric coated tablets of hot-melt extruded lansoprazole

The objective of this work was to use hot-melt extrusion (HME) technology to improve the physiochemical properties of lansoprazole (LNS) to prepare stable enteric coated LNS tablets. For the extrusion process, we chose Kollidon® 12 PF (K12) polymeric matrix. Lutrol® F 68 was selected as the plasticizer and magnesium oxide (MgO) as the alkalizer. With or without the alkalizer, LNS at 10% drug load was extruded with K12 and F68. LNS changed to the amorphous phase and showed better release compared to that of the pure crystalline drug. Inclusion of MgO improved LNS extrudability and release and resulted in over 80% drug release in the buffer stage. Hot-melt extruded LNS was physically and chemically stable after 12 months of storage. Both formulations were studied for compatibility with Eudragit® L100-55. The optimized formulation was compressed into a tablet followed by coating process utilizing a pan coater using L100-55 as an enteric coating polymer. In a two-step dissolution study, the release profile of the enteric coated LNS tablets in the acidic stage was less than 10% of the LNS, while that in the buffer stage was more than 80%. Drug content analysis revealed the LNS content to be 97%, indicating the chemical stability of the enteric coated tablet after storage for six months. HME, which has not been previously used for LNS, is a valuable technique to reduce processing time in the manufacture of enteric coated formulations of an acid-sensitive active pharmaceutical ingredient as compared to the existing methods.

Enhanced Solubility and Bioavailability of Pioglitazone Nanosuspension

Pioglitazone hydrochloride, a hypoglycemic agent, is a BCS class II drug with low solubility and thus, limited bioavailability. In the present study, nanosuspension of pioglitazone was prepared by high pressure homogenization using different stabilizers at different concentrations (0.25 to 3.0% wfv) and optimized and characterized for particle size, zeta potential, drug content, FT-IR and OSC analysis. The particle size of the optimized nanosuspension stabilized with 1% tween 80 (coded as NS17) was observed to be 433 nm and zeta potential of -36.76 mV indicated good physical stability. The nanoformulation was also found to be stable during storage of 30 days at 2-8 ·c. The optimized nanosuspension, NS17 showed increased solubility, ;n vitro dissolution rate and improved pharmacokinetics in Wistar rats as compared to the marketed formulation.

New Accelerating Stability Testing Protocol for O/W Emulsions Stabilized by Nonionic Surfactants Including Storage Temperature Determination

Betnovate®, Daktacort®, Daktarin®, Hemoclar®, Kenacomb® and Lotriderm® are O/W creams stabilized by nonionic surfactant/s and distributed in the Egyptian market without stability problems. In this work, the above creams were used as stability reference standard creams to extrapolate numeral values for the proposed parameters of the new accelerated stability testing protocol. The temperature–conductivity relations that represent all the above tested creams have strong direct linear relationships. Determination coefficient R2 values of these relations were ≥0.909 and their yield values represented as temperatures were ≥21o. The stability-indicating phase inversion temperatures of these creams were more than 80o. These common characteristic results represent the basis parameters of the new accelerating stability testing protocol as well as for the determination of the optimum storage temperature of the emulsion under examination. The applicability and validity of this protocol is confirmed by comparing the parameters results obtained from newly formulated O/W 2% miconazole nitrate cream to that obtained from the and also by subjecting all the tested O/W creams including the newly formulated one to accelerating stability testing studies according to the recent approved Issues of ICH Guidelines Q1A (R2). These accelerating stability studies include the measurements of the homogeneity, average weight and leakage test, drug content, pH, viscosity and microbiological analysis of the emulsion. Matching of the compared results and the approval of the stability testing studies confirms the applicability and validity of the new protocol. The new protocol determines the optimum storage temperature condition required for each cream under examination through the determination of the yield value represented as temperature of its temperature–conductivity relation.

Ceramide and N,N,N-Trimethylphytosphingosine-Iodide (TMP-I)-Based Lipid Nanoparticles for Cancer Therapy.

To evaluate the anti-tumor effect of ceramide or trimethylphytosphingosine-iodide (TMP-I) containing solid lipid nanoparticles (SLNs) prepared using trymyristin, phosphatidylcholine (PC), and Pluronic P85 (P85) for intravenous delivery of docetaxel. Docetaxel-loaded SLNs using ceramide or TMP-I at 3.22% (w/w) with a mean diameter of 89-137 nm were successfully prepared by high pressure homogenization. The prepared nanoparticles were characterized by particle size, zeta potential, drug content, and TEM analysis. Cellular uptake and cytotoxicity were studied using adriamycin-resistant breast cancer (MCF-7/ADR) cells. The optimized formulation's dissolution profile, pharmacokinetics, and antitumor effect in mice tumor model were compared with that of control (Taxotere(®)). The drug release rate of docetaxel from SLNs was lower than that of control (Taxotere(®)). The prepared SLNs showed higher cellular uptake of docetaxel compared to that of Taxotere(®) in MCF-7/ADR cell lines, which was further confirmed by the confocal laser scanning microscopy (CLSM) study using coumarin 6 (C6). Prepared SLNs exhibited significantly increased antitumor efficacy, compared to Taxotere(®), in MCF-7/ADR cells. In vivo pharmacokinetic study in rats (at 10 mg/kg dose) showed that the SLNs significantly reduced in vivo clearance of drug than Taxotere(®). Interestingly, ceramide and TMP-I SLNs efficiently inhibited the tumor growth compared to Taxotere(®) in MCF-7/ADR tumor xenografted mouse model. This work showed that TMP-I and ceramide SLNs not only significantly enhanced systemic exposure of drug, but also increased antitumor efficacy compared to Taxotere(®) and control SLN.

Design and Comparative Evaluation of In-vitro Drug Release, Pharmacokinetics and Gamma Scintigraphic Analysis of Controlled Release Tablets Using Novel pH Sensitive Starch and Modified Starch- acrylate Graft Copolymer Matrices.

The present investigation deals with the development of controlled release tablets of salbutamol sulphate using graft copolymers (St-g-PMMA and Ast-g-PMMA) of starch and acetylated starch. Drug excipient compatibility was spectroscopically analyzed via FT-IR, which confirmed no interaction between drug and other excipients. Formulations were evaluated for physical characteristics like hardness, friability, weight variations, drug release and drug content analysis which satisfies all the pharmacopoeial requirement of tablet dosage form. Release rate of a model drug from formulated matrix tablets were studied at two different pH namely 1.2 and 6.8, spectrophotometrically. Drug release from the tablets of graft copolymer matrices is profoundly pH-dependent and showed a reduced release rate under acidic conditions as compared to the alkaline conditions. Study of release mechanism by Korsmeyer's model with n values between 0.61-0.67, proved that release was governed by both diffusion and erosion. In comparison to starch and acetylated starch matrix formulations, pharmacokinetic parameters of graft copolymers matrix formulations showed a significant decrease in Cmax with an increase in tmax, indicating the effect of dosage form would last for longer duration. The gastro intestinal transit behavior of the formulation was determined by gamma scintigraphy, using (99m)Tc as a marker in healthy rabbits. The amount of radioactive tracer released from the labelled tablets was minimal when the tablets were in the stomach, whereas it increased as tablets reached to intestine. Thus, in-vitro and in-vivo drug release studies of starch-acrylate graft copolymers proved their controlled release behavior with preferential delivery into alkaline pH environment.

A transferable non-destructive method for the quantification of coronary stent coating components using Raman spectroscopy

Drug content of coronary stents is destructively evaluated using high pressure liquid chromatography. The method involves the dissolution of the coating from the stent into a solution and the analysis and quantification of the solvents' drug content. Quantification of the components of drug by Raman has been demonstrated with most recent methods using multivariate techniques. However, the calibration models generated as part of these methods are not easily transferable because they are developed using defined mixtures. In this work, we demonstrate a transferable non-destructive Raman method for the evaluation and quantification of the drug coating components by developing a model from the pure samples of the coating constituents. Using the designed experiment, the transferable Raman method is equivalence tested with the standard high pressure liquid chromatography approach and compares favorably as a non-destructive viable alternative. A method of dealing with the microheterogeneity of stent coatings is presented by spectral sample collection through the rotation of the stent. Knowledge of the coating formation and substrates is required in order to correctly interpret the results. Copyright © 2015 John Wiley & Sons, Ltd.

Tablet splitting: is it worthwhile? Analysis of drug content and weight uniformity for half tablets of 16 commonly used medications in the outpatient setting.

Tablet splitting is a well-established medical practice in clinical settings for multiple reasons, including cost savings and ease of swallowing. However, it does not necessarily result in weight-uniform half tablets. To (a) investigate the effect of tablet characteristics on weight and content uniformity of half tablets, resulting from splitting 16 commonly used medications in the outpatient setting and (b) provide recommendations for safe tablet-splitting prescribing practices. Ten random tablets from each of the selected medications were weighed and split by 5 volunteers (2 men and 3 women aged 25-44 years) using a knife. The selected medications were mirtazapine 30 mg, bromazepam 3 mg, oxcarbazepin 150 mg, sertraline 50 mg, carvedilol 25 mg, bisoprolol fumarate 10 mg, losartan 50 mg, digoxin 0.25 mg, amiodarone HCl 200 mg, metformin HCl 1,000 mg, glimepiride 4 mg, montelukast 10 mg, ibuprofen 600 mg, celecoxib 200 mg, meloxicam 15 mg, and sildenafil citrate 50 mg. The resulting half tablets were evaluated for weight and drug content uniformity in accordance with proxy United States Pharmacopeia (USP) specification (95%-105% for digoxin and 90%-110% for the other 15 drugs). Weight and drug content uniformity were assessed by comparing weight or drug content of the half tablets with one-half of the mean weight or drug content for all whole tablets in the sample. The percentages by which the weight and drug content of each whole tablet or half tablet differed from sample mean values were calculated. Other relevant physical characteristics of the 16 products were measured. A total of 52 of 320 half tablets (16.2%) and 48 of 320 half tablets (15.0%) fell outside of the proxy USP specification for weight and drug content, respectively. Bromazepam, carvedilol, bisoprolol, losartan, digoxin, and meloxicam half tablets failed the weight and content uniformity test; however, the half tablets for the rest of the medications passed the test. Mean percent weight loss after splitting was less than 1.5% for all drugs. Bromazepam, carvedilol, and digoxin showed the highest powdering loss during the tablet-splitting process. Tablet splitting could be safer and easier when drug- and patient-specific criteria have been met. Tablet size, shape, and hardness may also play a role in the decision to split a tablet or not. Tablets containing drugs with a wide therapeutic index and long half-life might be more suitable candidates for division. Dose variation exceeded a proxy USP specification for more than one-third of sampled half tablets of bromazepam, carvedilol, bisoprolol, and digoxin. Drug content variation in half tablets appeared to be attributed to weight variation due to fragment or powder loss during the splitting process.

Formulation and Evaluation of Mucoadhesive Microspheres of Tenofovir Disoproxil Fumarate for Intravaginal Use

Intravaginal mucoadhesive microspheres of tenofovir disoproxil fumarate (TDF) has been formulated using chitosan as the matrix-forming mucoadhesive polymer and evaluated. Ionotropic gelation method was used to produce the microspheres. Drug-polymer compatibility, percentage yield, particle size determination by optical microscopy, drug content & encapsulation efficiency, ex vivo mucoadhesion and in vitro release were evaluated. Based on the evaluation studies, F6 was selected as the best formulation and evaluated further for release kinetics and curve fitting analysis. F6 followed Korsmeyer-Peppas and Higuchi models. Accelerated stability study was conducted as per ICH guidelines. Drug content analysis, FTIR, XRD, SEM analysis showed that it remained stable for a period of six months.

English

In this study, an attempt was taken to enhance the solubility and dissolution characteristics of nifedipine, a poorly water soluble calcium channel blocking agent, by preparing solid dispersions (SD) with water soluble carriers; Poloxamer 407, HPMC 5 cPs, polyethylene glycol (PEG) 4000 and 6000 and surface solid dispersions (SSD) with insoluble carriers; sodium starch glycolate (SSG) and croscarmellose sodium (CCS). In vitro dissolution study showed that all the preparations were effective to improve the dissolution of nifedipine to several folds when compared with the drug and physical mixtures (PMs). Drug loading in SDs and SSDs was found uniform and they produced satisfactory results on drug content analysis (95 to 102%), compatibility and thermal analysis. PEG 6000, Poloxamer 407 and SSG were found to be the most effective carriers to enhance the dissolution behavior of nifedipine. SDs with water soluble carriers were found more effective in improving solubility of nifedipine than SSDs and PMs. Tablets were prepared using SDs and SSDs, and compared to marketed preparations and to a simple compressed tablet of nifedipine. Tablets prepared from SDs with PEG 6000 and Poloxamer 407 showed better release profile than all the marketed products.   Key words: Bioavailability, hydrophilic carrier, hydrophobic agents, interactions, solid matrix and compatibility.

Formulation and optimization of desogestrel transdermal contraceptive patch using crystallization studies

Levonorgestrel (LNG) is the most commonly used progestin in contraception. In this study, we report the use of an alternative progestin, desogestrel, for transdermal contraception. The drug was found to be significantly more permeable as compared to LNG (p<0.05). Crystallization studies were used to select the best adhesive among acrylate (Duro-Tak 87-4098 and Duro-Tak 87-202A) and polyisobutylene (PIB, Duro-Tak 87-608A) pressure sensitive adhesives by determining the drug's saturation solubility in them. The use of copovidone and mineral oil as formulation excipients was investigated to increase drug loading in the PIB adhesive. Physical characterization of the patches was performed using in vitro drug release, content analysis, patch weight and thickness variations and rolling ball tack and peel adhesion studies. Optimized patches were evaluated for in vitro transdermal delivery across hairless rat skin. The saturation solubility of desogestrel was found to be approximately 49.3% (w/w) and 55.6% (w/w) in Duro-Tak 87-4098 and Duro-Tak 87-202A acrylate adhesives, respectively. The saturation solubility of desogestrel was significantly lower (3-4%, w/w) in the PIB adhesive. Mineral oil (10%, w/w) and copovidone (30%, w/w) were found to be optimum for increasing drug loading and patch cosmetics. Results from the physical characterization studies suggest that a uniform and reproducible 7 day drug-in-adhesive patch could be developed.